Biomedical subjects

S Watanabe

Publications and source records attributed to S Watanabe.

At least 181 records · Page 10Linked to original sources

PubMed2001

Suppression of platelet-activating factor generation and modulation of arachidonate metabolism by dietary enrichment with (n-9) eicosatrienoic acid or docosahexaenoic acid in mouse peritoneal cells.

Several studies have shown that dietary n-3 polyunsaturated fatty acids (PUFAs) suppress platelet-activating factor (PAF) generation in leukocytes of humans and rodents, which is associated with the antagonism of arachidonic acid metabolism. Dietary eicosatrienoic acid (20:3n-9, ETrA) is also suggested to antagonize arachidonic acid (AA) metabolism, but its effect on PAF generation in leukocytes has not been defined. In the present study, we investigated the effects of an ETrA-rich diet on PAF generation and AA metabolism in mouse peritoneal cells, which were compared with those of a docosahexaenoic acid (DHA)-rich diet. Mice were fed a diet supplemented with a lipid preparation rich in ETrA, a DHA-rich fish oil (FO) or palm oil (PO) for 3 weeks, and peritoneal cells containing more than 80% of monocytes/macrophages were obtained. The peritoneal cells in the DHA and ETrA diet groups generated upon zymosan stimulation a smaller amount of PAF than cells in the PO diet group. In the peritoneal cells of the DHA diet group, AA contents in phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were significantly lower than those in cells of the PO diet group, but those in phosphatidylinositol (PI) were not significantly different between the two dietary groups. A considerable amount of ETrA was incorporated into the peritoneal cells of the ETrA diet group, and AA was reduced as compared with the PO diet group. These changes occurred preferentially in PI but to a less extent in PC and PE. The amount of free AA released by the peritoneal cells upon zymosan stimulation was significantly reduced in the DHA diet group as compared with that in the PO diet group, whereas AA release was similar between the PO and ETrA diet groups. In conclusion, the effects of dietary ETrA on AA content in the phospholipid subclasses and AA release were quite different from those of dietary DHA, although both diets suppressed PAF generation in mouse peritoneal cells to a similar extent.

Animals↗

PubMed2001

A phase I study of weekly docetaxel and cisplatin in advanced non-small cell lung cancer.

This phase I study was designed to determine the maximum tolerated dose (MTD) and toxicity of a weekly docetaxel (TXT) and cisplatin (CDDP) combination regimen in advanced non-small cell lung cancer (NSCLC). Patients with stage IIIB or IV NSCLC who were previously untreated were eligible. Docetaxel, at a starting dose of 20 mg m(-2) per week on days 1, 8 and 15, was combined with a fixed dose of cisplatin 80 mg m(-2) on day 1. Docetaxel was increased in 5 mg m(-2) per week steps. Chemotherapy was given in a 4-weeks cycle. Dose-limiting toxicities (DLTs) were defined as grade 3-4 leukopenia, thrombocytopenia, anemia, fever with grade 4 neutropenia and more than grade 2 non-hematologic toxicity, with the exception of nausea, vomiting, and alopecia. Omission of chemotherapy on day 8 and/or 15 was also considered DLT. Eighteen patients were enrolled in this study. Leukopenia, anemia and fatigue were the DLTs. No grade 4 toxicities were seen in any patients. The overall response rate was 44.4% (95% confidence interval, 21.5-67.4%). The recommended dose of TXT to be combined with CDDP 80 mg m(-2) on day 1 is 35 mg m(-2) per week on days 1, 8 and 15. This is a promising regimen, therefore a multicenter phase II study is now under way.

Aged↗

PubMed2001

MR imaging of murine arthritis using ultrasmall superparamagnetic iron oxide particles.

The objective of this work was to determine the ability of magnetic resonance (MR) imaging with ultrasmall superparamagnetic iron oxide (USPIO) particles to provide quantitative measures of inflammation in autoimmune arthritis. Mice were injected intravenously or intra-articularly with USPIO followed by magnetic resonance and histological assessment of the knee joint. Comparisons were made between MR microimages and histology in naïve mice and mice with collagen-induced arthritis.Following intravenous administration, accumulation of USPIO was observed in the popliteal lymph nodes, but not the joint. Administration of USPIO intra-articularly resulted in signal loss in the joint. The MR signal intensity could be quantified and correlated with iron staining in the synovial lining. A marked increase in USPIO uptake and a corresponding decrease in signal intensity were observed in arthritic, compared to naïve mice. Areas of focal signal loss corresponded to foci of iron staining by histology. These studies may provide a basis for the clinical application of USPIO in arthritis for assessing disease severity and monitoring response to therapy.

Animals↗

PubMed2001

Algebraic geometrical methods for hierarchical learning machines.

Hierarchical learning machines such as layered perceptrons, radial basis functions, Gaussian mixtures are non-identifiable learning machines, whose Fisher information matrices are not positive definite. This fact shows that conventional statistical asymptotic theory cannot be applied to neural network learning theory, for example either the Bayesian a posteriori probability distribution does not converge to the Gaussian distribution, or the generalization error is not in proportion to the number of parameters. The purpose of this paper is to overcome this problem and to clarify the relation between the learning curve of a hierarchical learning machine and the algebraic geometrical structure of the parameter space. We establish an algorithm to calculate the Bayesian stochastic complexity based on blowing-up technology in algebraic geometry and prove that the Bayesian generalization error of a hierarchical learning machine is smaller than that of a regular statistical model, even if the true distribution is not contained in the parametric model.

Algorithms↗

PubMed2001

Effects of quinapril on expression of eNOS, ACE, and AT1 receptor in deoxycorticosterone acetate-salt hypertensive rats.

Angiotensin II and nitric oxide (NO) may play a role in hypertensive cardiovascular remodeling. We evaluated the effects of long-term treatment with quinapril, an angiotensin converting enzyme (ACE) inhibitor, on expression of endothelial NO synthase (eNOS), ACE, and angiotensin II type 1 (AT1) receptor in the left ventricle and evaluated these relations to myocardial remodeling in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Deoxycorticosterone acetate-salt rats were induced with weekly injections of DOCA (30 mg/kg) and 1% saline in drinking water after right nephrectomy. Quinapril (DOCA-QUI, 10 mg/kg/day, subdepressor dose) or AT1 receptor antagonist TCV-116 (DOCA-TCV, 5 mg/kg/day, subdepressor dose) or vehicle (DOCA-V) were given after induction of DOCA-salt hypertension for 5 weeks, and age-matched sham-operated rats (ShC) served as a control group. The eNOS expression in the left ventricle were significantly decreased in DOCA-V compared with ShC, and were significantly increased in DOCA-QUI and DOCA-TCV compared with ShC and DOCA-V. The gene expression of ACE, AT1 receptor, and type I collagen mRNA were significantly increased in DOCA-V compared with ShC, and significantly suppressed in DOCA-QUI compared with DOCA-V. The DOCA-V rats demonstrated a significant increase of the wall-to-lumen ratio, perivascular fibrosis, and myocardial fibrosis, with all these parameters being significantly improved by quinapril. Myocardial remodeling in DOCA-salt hypertensive rats was significantly ameliorated by a subdepressor dose of quinapril, which may be due to an increase in eNOS mRNA and protein expression and a decrease in ACE and AT1 receptor mRNA expression in the left ventricle.

Angiotensin Receptor Antagonists↗

PubMed2001

Effect of dietary oils enriched with n-3 fatty acids on survival of mice.

Female mice were fed a conventional diet, shifted at 119 days of age to a diet supplemented with 10 wt % lard (Lar), high-linoleic (n-6) safflower oil (Saf), rapeseed oil (low-erucic, Rap), high-alpha-linolenic (n-3) perilla oil (Per) or a mixture (1:9) of ethyl docosahexaenoate (n-3) and soybean oil (DHA/Soy). Weight gain was less in the Per group than in the other groups at 497 days of age. In the Rap group, proteinuria was more severe than in the Saf, Per and DHA/Soy group, and hepatic triacylglycerol accumulation was greater than in the other groups. The mean survival time of the DHA/Soy group (753 days) was significantly longer than in the Lar group (672 days) and Saf group (689 days); the differences among other groups (e.g., 701 days in the Per group and 712 days in the Rap group) were not statistically significant. Although DHA is more susceptible to auto-oxidation than other major fatty acids in the air, an oil containing DHA was found to increase the survival of mice. Rapeseed oil that decreases the survival time of SHRSP rats was found to be safe in the mouse strain used in this study when survival was an end point.

Journal Article↗

PubMed2001

Synthesis and chain length-anti-HIV activity relationship of fully N- and O-sulfated homooligomers of tyrosine.

Fully N- and O-sulfated homooligomers from octamer to nonadecamer of tyrosine were obtained as their sodium salts, aO3S-[Tyr(SO3Na)]n-ONa (n = 8-19), from reaction mixtures of tyrosine with sulfur trioxide trimethylamine and pyridine comlexes, respectively, in pyridine. Their anti-HIV activity increased along with the increase of the chain length up to the dodecamer, maintained the same level to the length of the heptadecamer and then decreased. The maximal activity level was the same as or higher than that of dextran and curdlan sulfates.

Anti-HIV Agents↗

PubMed2001

Synthesis and anti-HIV activity of nonatyrosine N- and O1-9-decasulfate.

To develop a potent and effective anti-HIV compound with a definite polyanionic structure, synthesis of oligotyrosine sulfates by oligomerization with simultaneous sulfation of tyrosine was tried. One component was successfully isolated from the mixture containing many products as its sodium salt (Y-ART-4) and was identified as the salt of nonatyrosine N- and O1-9-decasulfate, NaO3S-[Tyr(SO3Na)]9-ONa. Anti-HIV activity of Y-ART-4, determined from the protection it provided against HIV-induced cytopathic effects, was almost the same with that of dextran sulfate and curdlan sulfate.

Anti-HIV Agents↗

PubMed2001

Should mediastinal nodal dissection be routinely undertaken in patients with peripheral small-sized (2 cm or less) lung cancer? Retrospective analysis of 225 patients.

OBJECTIVE: We retrospectively reviewed nodal status of the patients with peripheral small-sized lung cancer grouped by cell type and tumor size to evaluate the necessity of systematic nodal dissection in this group of patients. METHODS: From 1973 to 1998, 1713 patients underwent pulmonary resection for primary lung cancer in Kanazawa University. Among them, 225 patients (13.1%) with peripheral small-sized (2 cm or less) lung cancer underwent lobectomy and systematic nodal dissection were retrospectively reviewed. The maximum diameter of the tumor was measured on formalin-fixed surgical specimens. RESULTS: The histological types were adenocarcinoma in 170 (75.6%), squamous cell carcinoma in 20 (8.9%), small cell carcinoma in 19 (8.4%) and others in 16 (7.1%). Among 170 adenocarcinoma patients, 38 (22.4%) showed hilar or mediastinal lymph node metastases. No mediastinal lymph node metastasis was encountered in all squamous cell carcinoma (n = 20), adenocarcinoma < or = 1 cm (n = 16), small cell carcinoma < or = 1 cm (n = 4), and adenocarcinoma of Noguchi's classification type A or B (n = 24). CONCLUSIONS: Mediastinal nodal dissection would be unnecessary in the patients with peripheral small-sized lung cancer fulfilling these criteria: (1) squamous cell carcinoma < or = 2 cm; (2) adenocarcinoma < or = 1 cm; (3) localized bronchioloalveolar carcinoma < or = 2 cm without foci of active fibroblastic proliferation in histology (Noguchi's classification type A or B adenocarcinoma); (4) small cell carcinoma < or = 1 cm. Candidates fulfilling above criteria were 28.4% (64/225) of small-sized lung cancer and 10.9% of stage IA patients. The establishment of a universally accepted therapeutic strategy for small-sized lung cancer is indispensable in the clinical spread of various sort of limited resections.

Adenocarcinoma↗

PubMed2001

Predictive risk factors for postoperative tetany in female patients with Graves' disease.

BACKGROUND: Postoperative tetany occurs in patients with secondary hyperparathyroidism caused by a deficiency in calcium and vitamin D concomitant with transient hypoparathyroidism induced by surgery. In the present study, we further clarified the risk factors by referring to serum 25-hydroxyvitamin D [25(OH)D] and alkaline phosphatase. STUDY DESIGN: The serum levels of intact parathyroid hormone, calcium and other electrolytes, and 25-hydroxyvitamin D [25(OH)D] were measured preoperatively in 178 female patients with Graves' disease who underwent subtotal thyroidectomy. RESULTS: Of the 178 female patients, 15 (8.4%) developed tetany. Univariate analysis of 16 possible risk factors showed that 2 were statistically significant: serum 25(OH)D and alkaline phosphatase levels. The incidence of tetany according to the serum levels of 25(OH)D and alkaline phosphatase was 19.1% (9/47) in patients with 25(OH)D < or = 25 nmol/L and alkaline phosphatase > 155, 11.8% (4/34) in those with 25(OH)D < or = 25 nmol/L and alkaline phosphatase < or = 155, 6.7% (2/30) in those with 25(OH)D > 25 nmol/L and alkaline phosphatase > 155, and 0% (0/50) in those with 25(OH)D > 25 nmol/L and alkaline phosphatase < or = 155. CONCLUSIONS: Patients with Graves' disease who have vitamin D deficiency with high serum alkaline phosphatase levels are the highest-risk group for postoperative tetany. Serum 25(OH)D and alkaline phosphatase should be monitored in patients with Graves' disease.

Adolescent↗

PubMed2001

Development of a new enzyme-linked immunosorbent assay for the detection of anti-M2 in primary biliary cirrhosis.

We developed a new enzyme-linked immunosorbent assay (ELISA) for the detection of antimitochondrial antibody (AMA)-M2 in sera from patients with primary biliary cirrhosis (PBC), using 2-oxo-acid dehydrogenase complex (2-OADC) purified from porcine myocardium as the antigen source. The immunoreactivity was tested in a total of 354 sera, including 63 sera from patients with PBC by our ELISA. In the sera, indirect immunofluorescence for AMA, former ELISA for anti-pyruvate dehydrogenase complex (PDC) and immunoblot assay were performed, respectively. Of the 63 sera from patients with PBC, 51 sera (81.0%) were positive for anti-M2 in the new ELISA. Thirty-eight of the 63 sera (60.3%) were positive for anti-PDC in the former ELISA; the difference was significant between them (P=0.011). None of the 291 control sera from healthy volunteers showed reactivity against 2-OADC in the new ELISA. Moreover, in comparison with the results of immunoblot analysis, sensitivity and specificity in our ELISA to the sera from patients with PBC were 100 and 92.3%, respectively. Our results indicate that the new ELISA for anti-M2 using 2-OADC is simple, rapid and sensitive enough for the detection of AMA specific to PBC.

Journal Article↗

PubMed2001

Clinical investigation of endothelin-1 and nitric oxide in patients with portal hypertension focusing on plasma levels and immunohistological staining of liver tissues.

Plasma concentrations of endothelin-1 (ET-1) and nitrite/nitrate of patients with portal hypertension were measured. Sixteen patients with liver cirrhosis (the LC group) and 14 patients with idiopathic portal hypertension (the IPH group) and 12 healthy subjects (normal controls) were included in this study. The peripheral venous plasma concentration of ET-1 was significantly higher in the LC group (6.69+/-2.44 pg/ml) than in the IPH group (3.07+/-0.84 pg/ml) and normal controls (1.79+/-0.36 pg/ml), while the value in the IPH group was also significantly higher than that in normal controls. The peripheral venous plasma concentration of nitrite/nitrate was significantly higher in the LC group (67.7+/-38.9 &mgr;Mol/l) than in the IPH group (32.3+/-24.4 &mgr;Mol/l) and normal controls (26.1+/-9.8 &mgr;Mol/l). Hepatic venous plasma concentrations of ET-1 and nitrite/nitrate were measured in 8 patients from the LC group and 10 patients from the IPH group. The plasma concentration of ET-1 in the hepatic vein was significantly higher than that in the peripheral vein in both the LC and the IPH groups. The plasma concentration of nitrite/nitrate in the hepatic vein was significantly higher than that in the peripheral vein in the LC group. We also investigated the localization of ET-1, endothelin receptor (ET receptor) and nitric oxide synthase (NOS) in the liver tissue of LC patients (n=10), IPH patients (n=10) and normal controls (n=10). The expressions of ET-1, ET A receptors, ET B receptors, and inducive NOS (iNOS) were detected in patients with LC, and the labeling index (LI) was significantly higher than that in patients with IPH and normal controls. The expressions of ET-1, ET A receptors, and ET B receptors were found in patients with IPH, and the LI was significantly higher than that in normal controls. The expression of endothelial NOS (eNOS) was scarce in both LC and IPH patients. From these results, overproduction of ET-1 in the liver was regarded as one of the causes of the high plasma concentration of ET-1 in patients with LC and IPH. One of the causes of the high plasma concentration of nitrite/nitrate in LC was considered to be overproduction of nitric oxide (NO) in the liver. And we suggested that ET-1 is at a relatively higher density than NO in the hepatic sinusoid in LC and IPH.

Journal Article↗

PubMed2001

Hepatitis C virus core particle detected by immunoelectron microscopy and optical rotation technique.

Hepatitis C Virus (HCV) are 55-65 nm spherical particles, but the internal structure of the virion remains to be clarified. To clarify the morphology of HCV core particles, we performed an immune electron microscopy (IEM) using plasma samples from two blood donors with high HCV RNA titers and a detergent-treated anti-HCV core antibody-free plasma sample with high HCV RNA titer (1.5x10(8) copies/ml). Spherical particles, with 33-40 nm in diameter (an average diameter of 37 nm) were found in 1.22-1.25 g/ml fractions after sucrose density gradient centrifugation by conventional electron microscopy (EM). IEM using rabbit polyclonal antibody (RR8) specific to the putative HCV core protein and goat anti-rabbit IgG colloidal gold particles revealed that these spherical particles specifically reacted with RR8. This finding indicates that the spherical particles are naked HCV core particles. Some of the HCV core particles had an icosahedron-like structure. Optical rotation technique showed that the HCV core particle exhibits six-fold symmetry and that the length of regular hexagon side is approximately 20 nm. These findings showed that HCV core particles are spherical particles of 33-40 nm in diameter and that HCV core particles may possess an icosahedron-like structure and a buoyant density of 1.22-1.25 g/ml.

Journal Article↗

PubMed2001

Changes of middle latency somatosensory evoked potentials (SEPs) and alpha rythmicity associated with oculomotor processes.

OBJECTIVES: To evaluate median nerve somatosensory evoked potentials (SEPs) and alpha waves during different eye conditions. METHODS: Median SEPs and occipital electroencephalographs (EEG) were recorded in 6 eye conditions: eye-closed (EC), goggle (G), goggle+saccade (GS), saccade (S), eye-opened (EO) and pursuit (P), in 8 normal adults. Subjects saccaded their eyes reacting to auditory cues to watch a diode on the right or left side alternatively during the S condition, or imitated the same saccadic eye-movement as that in the S condition during the GS condition. In the P condition, subjects traced a small circle moving on a computer screen. RESULTS: Compared with the EC and G conditions, N30 (P25-N30 or P14-N30) amplitudes in C4' were significantly larger and the mean amplitude and power of the alpha band was significantly attenuated in the other 4 conditions. The amplitude and power of the alpha band differed significantly between the GS and S conditions, whereas N30 amplitudes were similar between the two conditions. N30-P45 or P45-N60 amplitudes in C4' were significantly larger in the P condition than in other conditions. CONCLUSIONS: Present findings suggest that different neural mechanisms cause alpha blocking and the modification of middle latency SEPs associated with oculomotor control.

Adult↗

PubMed2001

Feline ubiquitin fusion protein genes.

Using cDNA from a CRFK cell line as a template, PCR amplification was performed with the Ub1S and poly(dT) primers to isolate feline ubiquitin genes. Sequencing of the 495 bp PCR fragment revealed that the putative amino acids induced by this fragment gave a fusion protein consisting of a ubiquitin polypeptide (76 amino acids) and an extension protein of ribosomal proteins L40 (52 amino acids). The putative amino acid sequence of ubiquitin was identical to those of humans, rats and pigs. The recombinant glutathione S-transferase (GST)-feline ubiquitin fusion proteins were produced in Escherichia coli and purified. The fusion proteins had a molecular weight of about 42 kDa and were detected by immunoblot assay with rabbit anti-ubiquitin antiserum. The mRNAs from heat-shocked and non-heat-shocked cells were subjected to RT-PCR (Ub1S and poly(dT) primers) analysis. The molecular weights of the ubiquitinated proteins in heat-shocked CFRK cells were between 18 kDa and 24 kDa by immunoblot assay. These results suggested that there were more ubiquinated proteins in the heat-shocked CRFK cells than in the pre-heat-shocked cells.

Amino Acid Sequence↗

PubMed2001

Inherited factor H dysfunction and complement-associated glomerulonephritis in renal grafts of first and second transplantations.

A 38-yr-old man with factor H dysfunction and unknown glomerular disease received first and second renal transplantations (Tx) from living-related donors. His examination showed a low percentage activity of factor H (31%). Factor H dysfunction has been known to be associated with type II or III membranoproliferative glomerulonephritis (MPGN), haemolytic uraemic syndrome and IgA GN. The first graft from his mother showed diffuse mesangial deposit of IgA. His son has had IgA GN and his data also revealed a low percentage activity of factor H (33%). He and his son both showed a low activity of C3. Moreover, his father, who was the donor of the second Tx, had a low percentage activity of factor H (25%), and presented with mild glomerular deposit of C3 at operation, while he has been healthy through his entire 67 yr of life. Each of them had a low percentage activity of factor H. These findings through three generations suggested the inheritance of factor H dysfunction. The patient presented with proteinuria 3 months after the first Tx. At the first biopsy 30 months after the first Tx, light microscopy revealed minor glomerular abnormalities with electron dense deposits in subepithelial, intramembranous and mesangial regions, while immunofluorescence showed massive glomerular deposits of C3. In the second biopsy 51 months after the first Tx, the glomerulonephritis developed mesangial proliferation and crescent formation, accompanied by more massive C3 deposit and intramembranous, mesangial and subepithelial dense deposits. He then required redialysis. At the second and third biopsies within 2 months after the second Tx, the renal graft showed similar findings to the first biopsy after the first Tx. He perhaps presented with a recurrence of complement-associated GN, showing an atypical form of MPGN after Tx. These findings suggest that factor H dysfunction may play an important role of a certain pathogenesis of GN.

Adult↗

PubMed2001

Gangliosides GD1b, GT1b, and GQ1b suppress the growth of human melanoma by inhibiting interleukin-8 production: the inhibition of adenylate cyclase.

We studied the effects of various gangliosides on in vitro growth of human metastatic melanoma WM266-4. GD1b, GT1b, and GQ1b inhibited 3H-thymidine uptake and growth rate of WM266-4 whereas the other gangliosides were ineffective. The growth inhibition by GD1b, GT1b, and GQ1b was counteracted by interleukin-8 but not by the other growth factors. The growth inhibition by gangliosides was not detected in the presence of anti-interleukin-8 antibody. GD1b, GT1b, and GQ1b reduced the constitutive interleukin-8 secretion and mRNA levels in WM266-4. Transient transfection showed that GD1b, GT1b, and GQ1b inhibited the constitutive chloramphenicol acetyltransferase expression driven by interleukin-8 promoter in WM266-4. Transfection with a series of 5'-deleted mutants demonstrated that the sequences between -98 and -62 bp on interleukin-8 promoter may be involved in the transcriptional repression by these gangliosides. Cyclic AMP analog dibutyryl cAMP counteracted GD1b, GT1b, and GQ1b-induced inhibition of interleukin-8 production at the levels of protein secretion, mRNA expression, and promoter activity. GD1b, GT1b, and GQ1b reduced cAMP level and protein kinase A activity in WM266-4. These gangliosides suppressed adenylate cyclase activity without altering that of cyclic nucleotide phosphodiesterase in WM266-4. The data indicate that GD1b, GT1b, and GQ1b may suppress the growth of melanoma by inhibiting interleukin-8 production via the inhibition of adenylate cyclase.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2001

Anti-mycotics suppress interleukin-4 and interleukin-5 production in anti-CD3 plus anti-CD28-stimulated T cells from patients with atopic dermatitis.

It is reported that anti-mycotic agents are effective for the treatment of patients with atopic dermatitis. We studied the in vitro effects of anti-mycotics on T helper-1 and T helper-2 cytokine production in anti-CD3 plus anti-CD28-stimulated T cells from atopic dermatitis patients and normal donors. The amounts of interleukin-4 and interleukin-5 secreted by anti-CD3/CD28-stimulated T cells were higher in atopic dermatitis patients than in normal donors. Azole derivatives, ketoconazole, itraconazole, miconazole, and nonazole terbinafine hydrochloride, and tolnaftate reduced interleukin-4 and interleukin-5 secretion without altering that of interferon-gamma and interleukin-2 in anti-CD3/CD28-stimulated T cells from both atopic dermatitis patients and normal donors. The azole derivatives were more inhibitory than nonazole anti-mycotics. These anti-mycotics reduced the anti-CD3/CD28-induced mRNA expression and promoter activities for interleukin-4 and interleukin-5. The 3',5'-cyclic adenosine monophosphate analog dibutyryl 3',5'-cyclic adenosine monophosphate reversed the inhibitory effects of the anti-mycotics on interleukin-4 and interleukin-5 secretion, mRNA expression, and promoter activities. Anti-CD3/CD28 transiently (< or = 5 min) increased intracellular 3',5'-cyclic adenosine monophosphate in T cells, and the increase was greater in atopic dermatitis patients than in normal donors. The increase of 3',5'-cyclic adenosine monophosphate by anti-CD3/CD28 correlated with interleukin-4 and interleukin-5 secretion by anti-CD3/CD28. The transient 3',5'-cyclic adenosine monophosphate increase was suppressed by anti-mycotics, and azole derivatives were more suppressive than nonazoles. Azole derivatives inhibited the activity of cyclic adenosine monophosphate-synthesizing adenylate cyclase whereas terbinafine hydrochloride and tolnaftate enhanced the activity of 3',5'-cyclic adenosine monophosphate-hydrolyzing cyclic nucleotide phosphodiesterase in atopic dermatitis and normal T cells. These results suggest that the anti-mycotics may suppress interleukin-4 and interleukin-5 production by reducing 3',5'-cyclic adenosine monophosphate signal, and stress their potential use for the suppression of T helper-2-mediated allergic reactions.

Adenylyl Cyclases↗